rs112989722
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000138.5(FBN1):c.6354C>T(p.Ile2118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FBN1
NM_000138.5 synonymous
NM_000138.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.700
Genes affected
FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 15-48437347-G-A is Pathogenic according to our data. Variant chr15-48437347-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48437347-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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FBN1 | NM_000138.5 | c.6354C>T | p.Ile2118= | synonymous_variant | 52/66 | ENST00000316623.10 | |
FBN1 | NM_001406716.1 | c.6354C>T | p.Ile2118= | synonymous_variant | 51/65 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FBN1 | ENST00000316623.10 | c.6354C>T | p.Ile2118= | synonymous_variant | 52/66 | 1 | NM_000138.5 | P1 | |
FBN1 | ENST00000559133.6 | c.6354C>T | p.Ile2118= | synonymous_variant, NMD_transcript_variant | 52/67 | 1 | |||
FBN1 | ENST00000674301.2 | c.6354C>T | p.Ile2118= | synonymous_variant, NMD_transcript_variant | 52/68 | ||||
FBN1 | ENST00000537463.6 | c.*2117C>T | 3_prime_UTR_variant, NMD_transcript_variant | 27/31 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250630Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135414
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461330Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726970
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Marfan syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Oct 24, 2019 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 22, 2019 | The p.Ile2118Ile variant has been identified in 6 individuals with clinical features of Marfan syndrome and segregated in 7 affected relatives (Liu 1997, Miller 2007, Attanasio 2008, Pilop 2009, Pees 2014, Trujillo Quintero 2017). In addition, this variant has been identified as a de novo variant in one affected individual by our laboratory (paternity/maternity not confirmed). This variant has also been identified in 1/19938 East Asian and 1/128572 European chromosomes by gnomAD (gnomAD https://gnomad.broadinstitute.org/). Although this variant does not lead to an amino acid change, functional studies have shown that this variant induces the skipping of exon 51 leading to the in-frame deletion of 22 amino acids (Liu 1997). Therefore, this variant meets criteria to be classified as pathogenic. ACMG/AMP codes applied: PP1_Strong; PM2; PM6; PS3_Moderate; PS4. - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 11, 2014 | The c.6354C>T pathogenic mutation (also known as p.I2118I), located in coding exon 51 of the FBN1 gene, results from a C to T substitution at nucleotide position 6354. This nucleotide substitution does not change the amino acid at codon 2118. However, this alteration results in in-frame skipping of the entire exon 51 based on RT-PCR analysis (Liu W et al. Nat Genet. 1997;16(4):328-9). This recurrent alteration disrupts an exonic splicing enhancer and has been reported in multiple patients (Miller TE et al. Genet Med. 2007;9(1):23-33; Attanasio M et al. Clin Genet. 2008;74(1):39-46; Pilop C et al. Circulation. 2009;120(11):983-91; Pees C et al. Clin Genet. 2013). Based on the supporting evidence, c.6354C>T is interpreted as a disease-causing mutation. - |
Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 16, 2019 | Variant summary: FBN1 c.6354C>T results in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, multiple publication reports experimental evidence that this variant affects mRNA splicing (Liu_1997, Kashima_2007, Miller_2007). The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.6354C>T has been reported in the literature in multiple individuals affected with Marfan Syndrome (Liu_1997, Miller_2007, Attanasio_2008, Pilop_2009, Trujillo-Quintero_2017). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 27, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Published RT-PCR studies demonstrated that c.6354 C>T results in skipping of exon 52 (reported as exon 51) (PMID: 9241263); This variant is associated with the following publications: (PMID: 18435798, 24199744, 34550612, 37107549, 16995940, 11137998, 33801742, 34281902, 36729443, 17224687, 9241263, 28117189, 19720936) - |
Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 14, 2022 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 52 (also known as exon 51), but is expected to preserve the integrity of the reading-frame (PMID: 9241263, 16995940, 17224687, 17884807). ClinVar contains an entry for this variant (Variation ID: 16449). This variant has been observed in individual(s) with Marfan syndrome (PMID: 9241263, 17224687, 18435798, 19720936, 24199744, 28117189). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs112989722, gnomAD 0.005%). This sequence change affects codon 2118 of the FBN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -25
Find out detailed SpliceAI scores and Pangolin per-transcript scores at